S239: SOX11 DRIVES B1A LINEAGE COMMITMENT AND B1A/MCL-LIKE LYMPHOMA FORMATION IN MICE
Authors: Tim Pieters, Luca Pagliaro, Panagiotis Ntziachristos, Pieter Van Vlierberghe, Steven Goossens
Journal: HemaSphere (2023)

Background: Mantle cell lymphoma (MCL) is a highly aggressive B cell lymphoma that accounts for 6% of all non-Hodgkin lymphomas and is characterized by abnormal proliferation of mature antigen- naive B lymphocytes. Despite recent advances in patient risk stratification, MCL remains incurable due to frequent relapses and resistance to therapy. SOX11 is a key transcription factor in the pathogenesis of MCL and is highly expressed in conventional MCL, but it is not expressed in the normal B cells or in the indolent leukemic nonnodal MCL subtype. Aims: We want to investigate if SOX11 overexpression is sufficient to drive MCL-like lymphoma in mice. Furthermore, we want to identify the cell-of-origin of this murine MCL model and uncover the molecular mechanisms underlying SOX11-driven B1a/MCL-like lymphoma formation. Methods: Although SOX11 was identified as crucial oncogene that supports maintenance of MCL, its role in the initiation of MCL remains largely unknown. Here, we developed a novel mouse model for condition overexpression of SOX11 and a eGFP. We use different Cre-lines to activate SOX11 in pre-B cells or common lymphoid progenitors, or in a tamoxifen-dependent manner. Transplantation experiments are used to identify the cell-of-origin and asses B-cell reprogramming. We used a multi-omics (RNAseq, ATACseq, etc) approach to unravel SOX11-based transcriptional activity. Results: We found that elevated levels of SOX11 in B-cells are sufficient to drive MCL-like lymphomas in mice. Moreover, SOX11 expression synergized with loss of p53 and overexpression of Ccnd2 to form aggressive MCL-like CD19+CD5+CD23-IgM+IgD+ lymphomas, with a median survival of 314 (p53Mb1; n=11), 165 (SOX11/p53Mb1; n=19), and 134 (SOX11/Ccnd2/p53Mb1; n=15) days. These SOX11-driven lymphomas show transcriptional, immunophenotypic and functional similarities with both murine B1a cells and MCL patients. SOX11 overexpression skews B-cell development towards the B1a and marginal zone B-cell lineage and it block B2-cell development at the Pro-B and Pre-B cell stage, which coincides with onset eGFP that is a measure of expression of Cre and SOX11. In contrast to cyclin D2-driven MCL-like model, SOX11 is inducing a pre-lymphoma stage, in which there is a progressive accumulation of B1a cells in peripheral blood, peritoneal cavity, spleen and bone-marrow. The pre-lymphoma B1a cells have a BCR repertoire which was biased towards binding of self-antigens, such as phosphatidylcholine, and have increased BCR signaling activity. To prove that embryonic-derived B1a cells were the cell-of-origin of SOX11-driven MCL-like lymphoma, we transplanted CD19+ B-cells from SOX11/p53Mb1 fetal livers into secondary recipients and found that these embryonic cells could give rise to MCL-like lymphomas. Next, we wanted to determine how SOX11 is inducing the pre-lymphoma phase, either by expanding existing B1a cells, having a developmental bias towards B1a cells, or by the ability to reprogram B2-cells towards a B1a cell fate. Therefore, we crossed SOX11/p53 mice with a tamoxifen-inducible CreERT2 line and transplanted different sorted B1 and B2 subsets after a short tamoxifen induction ex vivo in immunocompromised mice. We found that SOX11 OE can redirect mature B2 cells to form B1a/MCL lymphomas. Summary/Conclusion: SOX11 is a key B1a lineage factor in mice and its aberrant expression is leading to the formation of MCL-like lymphomas in mice.Keywords: B cell development, Mantle cell lymphoma, Mouse model, B cell lymphoma